Lung cancer is the deadliest cancer worldwide, accounting for 27% of all cancer deaths. Squamous lung cancer is thought to develop in a stepwise fashion through premalignant intermediates, providing us with the opportunity to intervene before it becomes invasive. Therefore, a novel approach to cure patients of lung cancer is to develop a targeted chemoprevention strategy to prevent the formation of lung premalignant lesions (PMLs) in the first place. Previous work from our lab has demonstrated that lung premalignancy represents a state of excessive self-renewal of airway basal stem cells (ABSCs) following injury that is accompanied by a block in differentiation to the mucociliary epithelium. However, little is known about the mechanisms that govern ABSC proliferation in response to injury and their influence on PML formation. Using an in vivo injury model, Wnt signaling was observed to be necessary for the early proliferative phase of repair. Wnts were additionally secreted by both ABSCs and subepithelial fibroblasts of the intercartilaginous zone (ICZ), a poorly characterized niche in the proximal airway that can signal to ABSCs. These data suggest that dual autocrine and paracrine Wnt signaling promote repair. Further, excessive Wnt/?-catenin signaling drove ABSC hyperproliferation that resembled PMLs seen in patients, offering this pathway as tractable therapeutic target. High-throughput drug screening identified an unannotated Wnt signaling inhibitor, term Wnt Inhibitor Compound 1 (WIC1). allow the development of a novel chemoprevention strategy for lung premalignancy to prevent the excessive ABSC proliferation. The goal of this proposal is to a develop a nuanced understanding of ABSC homeostasis and interactions within the proximal airway epithelial niche and to make strides in formulating a novel chemoprevention strategy for lung premalignancy. Here, Specific Aim 1 will elucidate the roles of autocrine and paracrine Wnt/?-catenin signaling in injury repair in vivo. The necessity of autocrine Wnt signaling to drive repair will be assessed and the Wnt-secreting fibroblast cell population will be identified. Specific Aim 2 will analyze the role of WIC1 in airway repair and PML prevention in vivo. These studies will be conducted at the David Geffen School of Medicine at UC Los Angeles under the mentorship of sponsor Dr. Brigitte Gomperts, a highly accomplished investigator in lung premalignancy biology and airway homeostasis as well as co-sponsor Dr. Kathrin Plath, an expert in stem cell fate decisions and single cell transcriptomics. The important biology that is being addressed in this proposal likelihood that we will elucidate the regulatory mechanisms underlying proximal airway homeostasis and lung premalignancy. This, in turn, could inform our strategies for developing a novel targeted chemopreventive therapeutic and could set the stage for my future career as a physician scientist.